Malaria is a major infectious disease. Conservative estimates predict that 2-300 million people are afflicted and over a million children die from the infection each year. Plasmodium falciparum causes the most virulent form of human malaria. A striking feature of P. falciparum is its infection of the mature erythrocyte. Despite the fact that this is a non-endocytic host cell, its signaling protein such as the heterotrimeric Gs and G protein coupled receptors (GPCRs) regulate infection of P. falciparum. The overall objective of this project is to develop a detailed understanding of the molecular and cellular mechanisms by which P. falciparum and malaria parasites induce signaling in erythrocytes. It is anticipated that study will lead to understanding how signaling via the erythrocyte heterotrimeric Gs protein confers susceptibility to malarial infection and pathology and thereby contribute to understanding the basic biology of the parasite as well as disease. Molecular, microbial genetic tools using transfection, functional genomics combined with high resolution imaging techniques, biochemical assays as well as expertise in hematology and host genetics, will be used to investigate mechanisms that lead to vacuole formation, modify basic membrane properties of the host erythrocyte and confer resistance against malaria. The information gathered in these studies may be important to understanding mechanisms that underlie development of therapeutic strategies against malarial infection and hemolytic disorders.